The following paragraphs are not an admission that anything discussed in them is prior art or part of the knowledge of persons skilled in the art.
Bond-forming reactions are of widespread interest to synthetic chemists, especially those cross-coupling reactions that create new C—C, C—N, C—O, C—S, and C—P bonds. These reactions rely upon catalysts to improve the speed and yield of reaction. C—N cross-coupling is of particular significance in the pharmaceutical industry.
The palladium-catalyzed arylation of amines and related NH-containing substrates using (hetero)aryl (pseudo)halide coupling partners (i.e. Buchwald-Hartwig amination, BHA) has emerged as a method for the construction of C(sp2)-N bonds that is widely employed in the synthesis of pharmaceuticals, natural products, and functional materials on both benchtop and industrial scales.
In the early development of BHA, simple triarylphosphines were used as supporting ancillary ligands. However, in the ensuing years, it is now understood that ancillary ligands must be chosen so as to promote the formation of a monoligated, electron-rich Pd(0) complex that is activated towards (hetero)aryl (pseudo)halide oxidative addition, while also enabling C—N bond reductive elimination to afford the (hetero)aryl amine product. The steric demands of these two key mechanistic steps suggest the application of bulky ancillary ligands, to favor low-coordination and to encourage reductive elimination. However, the ancillary ligand electronic requirements for oxidative addition and reductive elimination are orthogonal, with strongly electron-donating ligands favoring oxidative addition, and less electron-donating ligands favoring reductive elimination. This has made selection of such ligands difficult.
Electron-rich ligands have in general proven to be most effective, especially in combination with substrates for which oxidative addition is challenging (e.g. less expensive and more abundant, but less reactive aryl chlorides). On the basis of these guiding principles, several diverse classes of bulky, electron-rich ancillary ligands have emerged for use in BHA, including: trialkylphosphines (e.g., cataCXium A); (hetero)biaryl monophosphines (e.g., Buchwald ligands, BippyPhos); bisphosphines (e.g., JosiPhos CyPF-tBu); P,N-ligands (e.g., Mor-DalPhos); and N-heterocyclic carbenes (e.g., IPr, IPent, and others). From a practical perspective, all of the above are commercially available and air-stable as the free-ligand or in pre-catalysts form, thus facilitating uptake by synthetic chemists. The development and application of these and other ancillary ligand families has enabled broad substrate scope in BHA chemistry, including challenging and diverse transformations ranging from the selective monoarylation of basic and nucleophilic species (e.g. ammonia and primary alkylamines) to the arylation of comparatively acidic substrates (e.g. amides and NH heterocycles). While some particularly versatile ancillary ligands have been identified, in most cases the selection of a strategically optimized ancillary ligand is required in order to achieve ideal results for a given substrate class in BHA.
Introduction
The following introduction is intended to introduce the reader to this specification but not to define any invention. One or more inventions may reside in a combination or sub-combination of the elements or steps described below or in other parts of this document. The inventors do not waive or disclaim their rights to any invention or inventions disclosed in this specification merely by not describing such other invention or inventions in the claims.
Notwithstanding the broad utility of BHA protocols, the expense and relatively low abundance of palladium, and the often costly nature of the required ancillary ligands, provide impetus for the development of first-row transition metal catalysts for C—N cross-couplings. The authors of the present disclosure believe that the smaller size and distinct electronic properties of the 3d metals, relative to palladium, may provide access to new and useful reactivity manifolds. Among first-row metals, copper-based catalysts have a particularly long-standing history in C—N cross-coupling chemistry. Unfortunately, copper-based catalysts reported to date for C—N cross-couplings have proven incapable of effecting transformations of low cost and wide availability (hetero)aryl chlorides or sulfonates.
The authors of the present disclosure believe that nickel catalysis offers promise as a competitive alternative to BHA protocols. It is significantly less expensive than palladium (e.g. in terms of the cost of simple MX2 salts, NiCl2<1$/g; PdCl2>$50/g). Conventional phosphine ancillary ligands employed in the early development of both BHA and related nickel-catalyzed reactions, including PPh3, rac-BINAP, and DPPF, are useful in some circumstances but have not been generally applicable. Ammonia monoarylation has been reported with the use of nickel complexes containing JosiPhos, however JosiPhos is an expensive, fullerene-containing reagent.
There remains a need to develop chemical catalysts which may be used to form C(sp2)-N bonds.
In some embodiments, the present disclosure provides a ligand for a catalyst or pre-catalyst. The catalyst or pre-catalyst may be a nickel-based catalyst or pre-catalyst. The ligand for the catalyst or pre-catalyst according to the present disclosure has a chemical formula as illustrated in Formula (I):

In a ligand according to Formula (I):
X is C, N, O or S;
Y is C or a bond;
one of Z1, Z2 and Z3 is
                when Z1 is        
then Z2 is P(AR1)(A′R2), and Z3 is H, alkyl, alkoxy, thioalkoxy, carboxy, carboxyalkyl, or halogen;                when Z2 is        
then one of Z1 and Z3 is P(AR1)(A′R2), and the other of Z1 and Z3 is H, alkyl, alkoxy, thioalkoxy, carboxy, carboxyalkyl, or halogen; and                when Z3 is        
then Z2 is P(AR1)(A′R2), and Z1 is H, alkyl, alkoxy, thioalkoxy, carboxy, carboxyalkyl, or halogen;
A and A′ are, independently: O or a bond;
R1 and R2 are, independently: aryl, alkyl, or cycloalkyl, where the aryl, alkyl or cycloalkyl is substituted or unsubstituted;
when X is C, then Y is C, and R3 and R4 are, independently: H, alkyl, alkoxy, thioalkoxy, carboxy, carboxyalkyl, or halogen;
when X is N and when Y is a C, then R3 is absent and R4 is: H, alkyl, alkoxy, thioalkoxy, carboxy, carboxyalkyl, or halogen;
when X is N and when Y is a bond, then R4 is absent and R3 is: H, aryl, or alkyl;
when X is O or S, then Y is a bond, and R3 and R4 are both absent;
R5 is: H, alkyl, alkoxy, thioalkoxy, carboxy, carboxyalkyl, or halogen; and
R6, R7, R8, and R9 are, independently, alkyl.
In other embodiments, the present disclosure provides a nickel-based catalyst or pre-catalyst that includes nickel complexed to a ligand according to the present disclosure.
In other embodiments, the present disclosure provides a method of forming a C(sp2)-N bond by reacting an aryl halide, a heteroaryl halide, an aryl pseudohalide, or a heteroaryl pseudohalide, with an amine-containing compound in the presence of a catalytically effective quantity of a nickel-based catalyst or pre-catalyst according to the present disclosure.